title: MnSOD activity regulates hydroxytyrosol-induced extension of chronological lifespan.
abstract: Chronological lifespan (CLS) is defined as the duration of quiescence in which normal cells retain the capacity to reenter the proliferative cycle. This study investigates whether hydroxytyrosol (HT), a naturally occurring polyphenol found in olives, extends CLS in normal human fibroblasts (NHFs). Quiescent NHFs cultured for a long duration (30-60 days) lose their capacity to repopulate. Approximately 60% of these cells exit the cell cycle permanently; a significant increase in the doubling time of the cell population was observed. CLS was extended in quiescent NHFs that were cultured in the presence of HT for 30-60 days. HT-induced extension of CLS was associated with an approximately 3-fold increase in manganese superoxide dismutase (MnSOD) activity while there was no change in copper-zinc superoxide dismutase, catalase, or glutathione peroxidase protein levels. Quiescent NHFs overexpressing a dominant-negative mutant form of MnSOD failed to extend CLS. HT suppressed age-associated increase in mitochondrial ROS levels. Results from spectroscopy assays indicate that HT in the presence of peroxidases can undergo catechol-semiquinone-quinone redox cycling generating superoxide, which in a cellular context can activate the antioxidant system, e.g., MnSOD expression. These results demonstrate that HT extends CLS by increasing MnSOD activity and decreasing age-associated mitochondrial reactive oxygen species accumulation.
authors.affiliation: Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242-1181, USA.
authors.forename: Ehab H
authors.initials: EH
authors.lastname: Sarsour
authors.forename: Maneesh G
authors.initials: MG
authors.lastname: Kumar
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kalen
authors.forename: Monali
authors.initials: M
authors.lastname: Goswami
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.forename: Prabhat C
authors.initials: PC
authors.lastname: Goswami
mesh_terms: D000375:Aging; D000975:Antioxidants / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008136:Longevity / Q000187:drug effects*; D008928:Mitochondria / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C005975:3,4-dihydroxyphenylethanol; D013482:Superoxide Dismutase; D011494:Protein Kinases; C413217:quiescence-induced kinase; D010626:Phenylethyl Alcohol